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SYNTHESIS OF 2,3-DISUBSTITUTED THIOPHENES FROM KETOALKYNES
A THESIS SUBMITTED TO
THE GRADUATE SCHOOL OF NATURAL AND APPLIED SCIENCES
OF
MIDDLE EAST TECHNICAL UNIVERSITY
BY
EROL CAN VATANSEVER
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR
THE DEGREE OF MASTER OF SCIENCE
IN
CHEMISTRY
DECEMBER 2013
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Approval of the thesis:
SYNTHESIS OF 2,3-DISUBSTITUTED THIOPHENES FROM
KETOALKYNES
submitted by EROL CAN VATANSEVER in partial fulfillment of the requirements
for the degree of Master of Sciences in Chemistry Department, Middle East
Technical University by,
Prof. Dr. Canan ÖZGEN ____________________
Dean, Graduate School of Natural and Applied Sciences
Prof. Dr. İlker ÖZKAN ____________________
Head of Department, Chemistry
Prof. Dr. Metin BALCI ____________________
Supervisor, Chemistry Dept., METU
Examining Committee Members:
Prof. Dr. Cihangir TANYELİ ____________________
Chemistry Dept., METU
Prof. Dr. Metin BALCI ____________________
Chemistry Dept., METU
Prof. Dr. Özdemir DOĞAN ____________________
Chemistry Dept., METU
Assist. Prof. Dr. Yasin ÇETİNKAYA ____________________
Chemistry Dept., Atatürk Üniversitesi
Assist. Prof. Dr. Akın AKDAĞ ____________________
Chemistry Dept., METU
Date: 26.12.2013
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I hereby declare that all information in this document has been obtained and
presented in accordance with academic rules and ethical conduct. I also declare
that, as required by these rules and conduct, I have fully cited and referenced
all material and results that are not original to this work.
Name, Last name : Erol Can Vatansever
Signature :
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ABSTRACT
SYNTHESIS OF 2,3-DISUBSTITUTED THIOPHENES FROM KETOALKYNES
Vatansever, Erol Can
M.Sc., Department of Chemistry
Supervisor: Prof. Dr. Metin Balcı
December 2013, 88 pages
Synthesis of thiophene containing compounds are of particular interest in synthetic
organic chemistry. Besides the importance for synthetic organic chemistry, thiophene
derivatives are used in applied research such as drug synthesis and study of
functional materials. In this thesis, a new methodology for developing of 2,3-
disubstituted thiophenes was developed. This methodology utilizes readily available
compounds in a two-step synthesis to provide a facile access to the 2,3-disubstituted
thiophenes. In the first step, ketoalkynes were prepared by Sonogashira coupling of
readily available acyl chlorides and terminal alkynes. Then they were reacted with
2,5-dihydroxy-1,4-dithiane in the presence of triethylamine to yield alcohol
intermediates. Finally, alcohol intermediates were dehydrated by treatment with
silica gel to yield 2,3-disubstituted thiophenes.
Keywords: Acyl-chloride, terminal alkyne, 2,3-disubstituted thiophene, ketoalkyne,
Sonogashira coupling
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ÖZ
2,3-DİSÜBSİTÜTE TİYOFENLERİN KETOALKİNLER ÜZERİNDEN
SENTEZLENMESİ
Vatansever, Erol Can
Yüksek Lisans, Kimya Bölümü
Tez Yöneticisi: Prof. Dr. Metin Balcı
Aralık 2013, 88 sayfa
Tiyofen içeren moleküllerin sentezi, sentetik organik kimyada önemli bir yere
sahiptir. Sentetik organik kimyanın yanı sıra, tiyofen içeren bileşikler, ilaç sentezi ve
diğer farklı malzemeler içinde kullanılmaktadır. Bu çalışmada, 2,3-disübsitüte
tiyofen bileşiklerinin sentezi için yeni bir yöntem geliştirildi. Bu yöntemde, kolayca
temin edilebilen başlangıç maddeleri kullanılarak, iki basamaklı sentez sonunda 2,3-
disübsitüte tiyofen bileşikleri sentezlendi. İlk basamakta açil klorür ve alkin
bileşiklerinden Sonogashira kenetlenmesi yöntemi ile ketoalkin bileşikleri elde
edildi. Daha sonra bu bileşiklerin, trietil amin varlığında 2,5-dihydroxy-1,4-dithiane
ile tepkimesinden dihidrotiyofen ara ürünleri elde edildi. Son kademede, bu ürünlerin
silika jel ile muamele edilmesi sonucunda su eliminasyonu sağlanarak, 2,3-
disübsitüte tiyofen bileşikleri elde edildi.
Anahtar kelimeler: Açil klorür, alkin, 2,3-disübsitüe tiyofen, ketoalkin, Sonogashira
kenetlenmesi
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ACKNOWLEDGEMENTS
I would like to thank my supervisor Prof. Dr. Metin Balcı for his valuable guidance,
advices and support throughout this work. I would like to express my deep gratitude
to Prof. Dr. Metin Balcı for giving me the chance to work in his group after the
unexpected loss of Prof. Dr. Ayhan Sıtkı Demir.
I would also like to thank Prof. Dr. Ayhan Sıtkı Demir who was unexpectdly passed
away while I was working under his supervision. I believe working with Prof. Demir
considerably expanded my vision.
I also thank to Assist. Prof. Dr. Nurettin Mengeş for his guidance and encouraging
attitude towards me.
I would like to express my thanks to all the members of Balcı Research Group; Selbi,
Sinem, Nalan, Yasemin, Merve, Tolga, Selin, Fatih, Başak, Sultan, Furgan, Emre,
Serdal and Özlem and Ayhan Sıtkı Demir Research Group; Melek, Seda, Ceren,
Eylem, Gökçil, Kıvanç, Ezgi, Serkan, Mehmet, Arif, Hussein, Duygu, Sinan for their
friendly attitude.
I thank to Merve Sinem Özer for her close friendship and helps.
I wish to express my eternal gratitude to my parents Nurhan and Ali Vatansever, for
their continuous support and encouragement during this work.
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TABLE OF CONTENTS
ABSTRACT ............................................................................................................................. v
ÖZ............................................................................................................................................ vi
ACKNOWLEDGEMENTS ................................................................................................... vii
TABLE OF CONTENTS ...................................................................................................... viii
LIST OF FIGURES ................................................................................................................. xi
LIST OF SCHEME ............................................................................................................... xiii
CHAPTERS
1. INTRODUCTION ................................................................................................................ 1
1.1 Heteroaromaticity ........................................................................................................... 1
1.2 Thiophene ....................................................................................................................... 2
1.3 Addition of thiol/thiolate nucleophiles to α,β-unsaturated carbonyl compounds ........... 4
1.4 Cascade reactions of α-thiolated carbonyl compounds with α,β-unsaturated carbonyl
compounds for accessing di/tetrahydrothiophene structures ................................................ 8
1.5 Michael addition of thiol compounds to α,β-alkynyl carbonyl compounds ................. 12
1.6 Fiesselmann Thiophene Synthesis ................................................................................ 13
1.6.1 Mechanism of the reaction between thioglycolic acid α,β-alkynyl carbonyl
compounds: .................................................................................................................... 14
1.6.2 Histroical view of Fiesselmann thiophene synthesis: ............................................ 16
1.6.3 New applications of Fiesselmann synthesis: ......................................................... 17
1.7 Synthesis of 2,3-disubstituted thiophenes by cyclization reactions ............................. 19
1.8 Aim of the thesis........................................................................................................... 21
2. RESULTS AND DISCUSSION ........................................................................................ 23
2.1 Synthesis of starting materials ...................................................................................... 23
2.1.1 Mechanism for Sonogashira coupling ................................................................... 24
2.1.2 Interpretation of polarization of alknyl carbon atoms by 13
C NMR chemical shift
differences ...................................................................................................................... 25
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2.2 Synthesis of the 2,3-disubstituted thiophenes from ketoalkynes ................................. 27
2.3 Mechanistic considerations on the reaction between 2,5-dihydroxy-1,4-dithiane and
ketoalkyne .......................................................................................................................... 28
2.3.1 First pathway ............................................................................................................. 28
2.3.2 Second Pathway ........................................................................................................ 31
2.3.3 Evaluation of the two pathways ................................................................................ 31
2.4 Stability of the alcohol intermediates ........................................................................... 33
2.5 Hydrolysis of trimethyl silyl group .............................................................................. 35
3. CONCLUSION .................................................................................................................. 37
4. EXPERIMENTAL ............................................................................................................. 41
4.1 General ......................................................................................................................... 41
4.2 General procedure for the synthesis of ketoalkyne derivatives 104-109 ..................... 42
4.2.1 4,4-Dimethyl-1-phenylpent-1-yn-3-one (104): ..................................................... 42
4.2.2 1,3-Diphenylprop-2-yn-1-one (105) ..................................................................... 43
4.2.3 1-(Naphthalen-2-yl)-3-phenylprop-2-yn-1-one (106) ........................................... 43
4.2.4 1-Phenylhept-2-yn-1-one (107) ............................................................................. 44
4.2.5 1-Phenylprop-2-yn-1-one (108) ............................................................................ 44
4.2.6 1-Phenyl-3-(trimethylsilyl)prop-2-yn-1-one (109) ............................................... 45
4.3 General procedure for the synthesis of 2,3-disubstituted thiophene derivatives 110-115
........................................................................................................................................... 45
4.3.1 2,2-Dimethyl-1-(2-phenylthiophen-3-yl)propan-1-one (110) ............................... 46
4.3.2 Phenyl(2-phenylthiophen-3-yl)methanone (111) .................................................. 46
4.3.3 2-Naphtyl(2-phenylthiophen-3-yl)methanone (112) ............................................. 47
4.3.4 (2-Butylthiophen-3-yl)(phenyl)methanone (113) ................................................. 47
4.3.5 Phenyl(thiophen-3-yl)methanone (114) ................................................................ 48
4.3.6 Phenyl(2-(trimethylsilyl)thiophen-3-yl)methanone (115)..................................... 48
REFERENCES ...................................................................................................................... 49
APPENDIX
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A. SPECTRAL DATA ........................................................................................................... 50
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LIST OF FIGURES
Figure 1 1H NMR spectrum of the alcohol intermediate 142...…………………….33
Figure A1 1H NMR spectrum of compound 104 ..................................................... 53
Figure A2 13
C NMR spectrum of compound 104 .................................................... 54
Figure A3 IR spectrum of compound 104 ................................................................ 55
Figure A4 1H NMR spectrum of compound 105 ..................................................... 56
Figure A5 13
C NMR spectrum of compound 105 .................................................... 57
Figure A6 IR spectrum of compound 105 ................................................................ 58
Figure A7 1H NMR spectrum of compound 106 ..................................................... 59
Figure A8 13
C NMR spectrum of compound 106 .................................................... 60
Figure A9 IR spectrum of compound 106 ................................................................ 61
Figure A10 1H NMR spectrum of compound 107 ................................................... 62
Figure A11 13
C NMR spectrum of compound 107 .................................................. 63
Figure A12 IR spectrum of compound 107 .............................................................. 64
Figure A13 1H NMR spectrum of compound 108 ................................................... 65
Figure A14 13
C NMR spectrum of compound 108 .................................................. 66
Figure A15 IR spectrum of compound 108 .............................................................. 67
Figure A16 1H NMR spectrum of compound 109 ................................................... 68
Figure A17 13
C NMR spectrum of compound 109 .................................................. 69
Figure A18 IR spectrum of compound 109 .............................................................. 70
Figure A19 1H NMR spectrum of compound 110 ................................................... 71
Figure A20 13
C NMR spectrum of compound 110 .................................................. 72
Figure A21 IR spectrum of compound 110 .............................................................. 73
Figure A22 1H NMR spectrum of compound 111 ................................................... 74
Figure A23 13
C NMR spectrum of compound 111 .................................................. 75
Figure A24 IR spectrum of compound 111 .............................................................. 76
Figure A25 1H NMR spectrum of compound 112 ................................................... 77
Figure A26 13
C NMR spectrum of compound 112 .................................................. 78
Figure A27 IR spectrum of compound 112 .............................................................. 79
Figure A28 1H NMR spectrum of compound 113 ................................................... 80
Figure A29 13
C NMR spectrum of compound 113 .................................................. 81
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Figure A30 IR spectrum of compound 113 .............................................................. 82
Figure A31 1H NMR spectrum of compound 114 ................................................... 83
Figure A32 13
C NMR spectrum of compound 114 .................................................. 84
Figure A33 IR spectrum of compound 114 .............................................................. 85
Figure A34 1H NMR spectrum of compound 115 ................................................... 86
Figure A35 13
C NMR spectrum of compound 115 .................................................. 87
Figure A36 IR spectrum of compound 115 .............................................................. 88
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LIST OF SCHEME
Scheme 1 Resonance structures of thiophene…………………...…………………...2
Scheme 2 α (alpha) and β (beta) positions of an unsaturated carbonyl compound…..4
Scheme 3 Addition reaction of methanethiol (11) to acrolein (12)…………………..5
Scheme 4 Two activation modes of Michael addition reaction…………...…………5
Scheme 5 Addition of benzene thiol (15) to 2-cyclopenten-1-one (14)……………...6
Scheme 6 General mechanism for Lewis acid catalyzed Michael addition
reactions……………………………………………………………………………....7
Scheme 7 Enantioselective benzene thiol (15) addition to 2-cyclohexen-1-one (21)..7
Scheme 8 Enantioselective benzyl thiol (25) addition to α,β,γ-unsaturated carbonyl
compound (24)………………………………………………………………………..8
Scheme 9 2,5-Dihydroxy-1,4-dithiane (31) is a dimer form of 2-
mercaptoacetaldehyde (32)…………………………………………………………...9
Scheme 10 Reaction of 2,5-dihydroxy-1,4-dithiane (31) and acrolein (12) ………….9
Scheme 11 Mechanism for reaction between 2-mercaptoacetaldehyde (32) and
acrolein (12)……..…………………………………………………………………..10
Scheme 12 Formation route of a dihydrothiophene 36 structure..……......……..….11
Scheme 13 Formation of compound 39 from 37……………………………………11
Scheme 14 Enantioselective synthesis of tetrahydrothiophene structure 42...……...11
Scheme 15 Enantioselective synthesis of nitro group containing tetrahydrothiophene
structure 46…………………………………………………………………………..12
Scheme 16 Study by Truce et al. indicating the substrate scope of the reaction……13
Scheme 17 Brief examples for substrate scope of Fiesselmann synthesis………….14
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Scheme 18 First part of the mechanism of Fiesselmann synthesis…………...…….15
Scheme 19 Second part of the mechanism of Fiesselmann synthesis………………16
Scheme 20 Woodward's synthesis of tetrahydrothiophene ring 64...………...……..16
Scheme 21 Hendrickson's general synthesis for heterocyclic ring construction……17
Scheme 22 Two alternative methods for accessing oligothiophenes 75, 78 by
Fiesselmann synthesis...……………………………………………………………..18
Scheme 23 Fiesselmann synthesis of 80 from 79 with an inorganic base…………..18
Scheme 24 Synthesis of benzothiophene (83) under harsh conditions...….…..........19
Scheme 25 Synthesis of benzothiophene (83) under milder conditions……....…….19
Scheme 26 Synthesis of 3-Substituted-2-aminothiophenes 89……………......……20
Scheme 27 Synthesis of thiophene 95…………………………...………………….20
Scheme 28 Synthesis of 2,3 dimethyl thiophene (97)………...…………………….21
Scheme 29 Synthesis of ketoalkynes…………………………………………….….21
Scheme 30 Synthesis of 2,3-disubstituted thiophenes from ketoalkynes……….......21
Scheme 31 Readily available starting compounds………...………………………..22
Scheme 32 Synthesis of ketoalkynes by Sonogashira coupling…………………….23
Scheme 33 Sythesized ketoalkynes.………………………………………..……….23
Scheme 34 Catalytic cycle for Sonogashira coupling………...……….……………24
Scheme 35 Synthesis of 2,3-disubstituted thiophenes………………………...…….26
Scheme 36 Synthesized 2,3-disubstituted thiophenes................................……...……26
Scheme 37 Base induced fragmentation of 2,5-Dihydroxy-1,4-dithiane (31)..…….27
Scheme 38 Formation of thio acetal 119 intermediate…………...……….………...28
Scheme 39 Formation of alcohol 122 intermediate…………….…………………...28
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Scheme 40 An inoperative mechanism for enolization of 119……………..……….29
Scheme 41 Reaction of 126 with 56………………………………………..……….29
Scheme 42 Suggested mechanism for formation of 129 ………………………..….30
Scheme 43 Second pathway for formation of alcohol intermediates 122………….30
Scheme 44 The equilibrum reaction of 133 and 134………………....……………..31
Scheme 45 Reaction between 68 and 130……………………...…………………...32
Scheme 46 Formation of thiophene 141 from alcohol intermediates 122 ……..…...32
Scheme 47 Possible hydrolysis pathway for compounds 109 and 115…………......34
Scheme 48 Synthetic scheme for synthesis of ketoalkynes 104-109……………….37
Scheme 49 Synthesis of 110–114…………………………………………………..38
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CHAPTER 1
INTRODUCTION
1.1 Heteroaromaticity
The term heteroaromaticity is used for the heterocyclic compounds having aromatic
structure. Due to their structural features, heteroaromatic compounds are highly
abundant in nature. In a review article published in 2000, it is stated that among the
chemical compounds identified to that time, about half of the known compounds had
heteroaromatic structure.1
Although presence of a heteroatom in a ring structure is sufficient to denote a
compound as heterocyclic, the situation is far more complex for designation of a
compound as aromatic. Basically, four criteria that are known as Hückel’s rules
should be met.
Furthermore, aromatic compounds that obey all Hückel’s rules also differ in their
degree of aromaticities due to unique electronic nature of these compounds.
To determine the degree of aromaticity, both theoretical and experimental methods
are developed. The results of a qualitative experimental determination based on
hydrogenation enthalpies of the aromatic compounds are shown below.1
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Table 1 Dewar resonance energy values for benzene, thiophene and furan
The Table 1 illustrates the relative aromaticities of benzene and three common five-
membered heterocyclic compounds. Dewar Resonance Energy (DRE) values indicate
the stabilization gained by the aromatic structure with respect to the compounds
unsaturated analogs. Therefore larger DRE values indicate greater stability gained by
aromaticity.
1.2 Thiophene
Thiophene (1) is an aromatic five-membered heterocyclic compound. Although there
are both some computational2,3
and experimental results3 suggesting pyrrole is more
aromatic than thiophene, the generally accepted order for the aromaticity of
thiophene is being between the aromaticites of benzene and pyrrole.1,2,4
Scheme 1 depicts resonance structures of unsubstituted thiophene. According to
theoretical calculations, the electron density on carbons 2 and 5 are more intense than
carbons 3 and 4 of thiophene.5
That result is in agreement with the reactivity profile
of thiophene towards nucleophiles. This phenomenon can be rationalized by
considering stability gained by the proximity of counterions.
Scheme 1 Resonance structures of thiophene
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Thiophene moieties are encountered in natural products. Echinothiophene (2),
isolated from the roots of Echinops grijissii, has benzothiophene moiety in its
structure.6 Moreover, Xanthopappins A (3) isolated from Xanthopappus subacaulis
has a thiophene acetylene structure.7 Another thiophene polyacetylene example is
Echinopsacetylenes A (4) that is isolated from the roots of Echinops Transiliensis.8
Thiophene containing molecular structures are also used in medicinal chemistry. For
example; Duloxetine (5), a drug marketed by Eli Lilly that is used as an anti-
depressant agent,9 has thiophene moiety in its molecular structure. Moreover
compound 6 has shown inhibition of the catalytic activity of HIV PR.10
Compound 7
was found to be effective in acute hypoxia-induced pulmonary hypertension in rats.11
Moreover, thiophene containing polymers are extensively used in materials
chemistry. Compund 8 is designed as a medium band-gap photovoltaic device12
and
compound 9 is a fluorescent biosensors that is used for selective detection of nucleic
acids.13
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1.3 Addition of thiol/thiolate nucleophiles to α,β-unsaturated carbonyl
compounds
Thiols are highly nucleophilic compounds owing to their great tendency for
polarization. For instance, according to experimental studies conducted based on rate
constants, n-propyl thiolate anion is found to be even more nucleophilic than
compounds showing α-effect like hydroxylamine.14
Moreover, both thiols and thiolates can be classified as soft bases due to their high
polarizability and relatively low electronegativity. At the same time having high
nucleophilicity and soft base nature, alkyl thiols are good nucleophiles for Michael
Addition reactions. Due to the their soft base nature thiols and thiolates prefer to
attack an α,β-unsaturated carbonyl compound 10 from β-position (Scheme 2).
Scheme 2 α (alpha) and β (beta) positions of an unsaturated carbonyl compound
Addition of alkyl and aryl thiols/thiolates to α,β-unsaturated carbonyl compounds is
extensively studied in the literature.
For example, the compound 13 was formed by addition of methanethiol (11) to
acrolein (12) at 0 oC in 41% yield. Compound 13 is important because; it is the
precursor of amino acid methionine (Scheme 3).15
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Scheme 3 Addition reaction of methanethiol (11) to acrolein (12)
Brønsted acids16
and Brønsted bases17,18
are frequently used as catalysts in Michael
addition of alkyl or aryl thiol compounds to α,β-unsaturated carbonyl compounds.
Brønsted acids increase the rate of reaction via activation of the electrophile whereas;
Brønsted bases operate by activating the nucleophile. Scheme 4 depicts how these
activation modes are achieved.
Scheme 4 Two activation modes of Michael addition reaction
The studies done with the aromatic thiols as nucleophiles are shown to be highly
solvent dependent. The reaction between 2-cyclopenten-1-one (14) and benzene thiol
(15) afforded product 16 in 6% yield in dichloromethane after 2 days (Scheme 5).19
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Scheme 5 Addition of benzene thiol (15) to 2-cyclopenten-1-one (14)
In another study, same reaction was carried out in water as the solvent. Interestingly,
the reaction was completed in 5 min. with 90% yield at room temperature. The
authors proposed, that the role of water may be the activation of both electrophile
and nucleophile. Hydrogen of a water molecule may form a hydrogen bond with
oxygen present in the 2-cyclopenten-1-one (14). So, this will withdraw the electrons
of 2-cyclopenten-1-one (14) towards water molecule and will activate the
electrophile.
Moreover, the oxygen of the same water molecule may form hydrogen bonding via
accepting hydrogen from the acidic proton of benzenethiol (15) therefore, activating
the nucleophile. As a result, the rate of the reaction was accelerated.20
Furthermore it is shown that, also in the presence of Lewis acids like Cu(OAc)2,21
InBr3,19
FeCl3,22
ceric ammonium nitrate,23
iodine24
the addition of thiol groups to
α,β-unsaturated carbonyl compounds was also studied. General mechanism for Lewis
acid catalyzed reactions begin with activation of compound 17 with Lewis acid.
Then, benzenethiol (15) attacks the β-carbon atom of compound 17. After proton
transfer, enol structure 19 is formed. Then, by tautomerisation the keto structure 20 is
formed (Scheme 6).
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Scheme 6 General mechanism for Lewis acid catalyzed Michael addition reactions
Enantioselective synthesis with chiral catalysts was also studied.25,26
When a chiral
cinchona alkaloid-derived urea 22 was used as a base the product 23 was formed in
quantitative yield and in 99% ee.26
The bifunctional catalyst 22 was used to activate both benzene thiol (15) and 2-
cyclohexen-1-one (21). The catalyst activates 21 by forming hydrogen bonds
between the hydrogen atoms present in urea moiety of 22 and carbonyl compound
21. Activation of benzene thiol (15) done by abstraction of the proton of 15 by
tertiary amine functionality of 22. Furthermore, enantioselectivity is achieved by the
chirality of the bifunctional catalyst 22 (Scheme 7).
Scheme 7 Enantioselective benzene thiol (15) addition to 2-cyclohexen-1-one (21)
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8
Another interesting Michael addition reaction was observed with α,β,γ-unsaturated
carbonyl compound 24 as an electrophile.27
In this application, benzyl-thiol (25) was
used as the nucleophile, quinine derived amine compound 26 served as the catalyst,
besides BOC protected amino acid 27 as the co-catalyst.
Amine functionality present in the quinine derived amine catalyst 26 forms highly
reactive imminium intermediate with compound 24. Afterwards, addition of
benzylthiol (25) gives the desired compound 26 with 91% conversion and 91% ee
(Scheme 8).
Scheme 8 Enantioselective benzyl thiol (25) addition to α,β,γ-unsaturated carbonyl
compound (24)
1.4 Cascade reactions of α-thiolated carbonyl compounds with α,β-unsaturated
carbonyl compounds for accessing di/tetrahydrothiophene structures
2,5-Dihydrotihophene (29) and tetrahydrothiophene (30) structures are saturated
analogues of thiophene. They differ from each other in their degree of unsaturation.
Synthesis of 2,5-dihydrothiophene (29) and tetrahydrothiophene (30) molecular
structures are also studied in the literature.28-33
The reactions listed in this part can be
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called as cascade reactions because; in each case there are two consecutive reactions
taking place to form the final product.
1.4.a. Construction of dihydrothiophene/tetrahydrothiophene ring through
reaction between α-thiolated carbonyl compounds and α,β-unsaturated
carbonyl compounds
A convenient method for the synthesis of dihydrothiophene (29) analogues is to use
2,5-dihydroxy-1,4-dithiane (31) as a precursor of 2-mercaptoacetaldehyde (32)
(Scheme 9). The reaction between 2,5-dihydroxy-1,4-dithiane (31) and acrolein (12)
forms compound 33 in 64% yield (Scheme 10).28
Scheme 9 2,5-Dihydroxy-1,4-dithiane (31) is a dimer form of 2-
mercaptoacetaldehyde (32)
Scheme 10 Reaction of 2,5-dihydroxy-1,4-dithiane (31) and acrolein (12)
10
10
Scheme 11 Mechanism for reaction between 2-mercaptoacetaldehyde (32) and
acrolein (12)
Mechanism of this reaction begins with addition of 2-mercaptoacetaldehyde (32) to
acrolein (12). After the proton transfer, acyclic compound 32-a is formed (Scheme
11). Then, the intramolecular aldol reaction gives cyclic compound 32-b. Finally,
spontaneous loss of water yields dihydrothiophene structure 33.
Furthermore, the substrate scope of electrophile is not limited with aldehydes, α,β-
unsaturated esters,29-30
nitro olefins,31,33
α,β-unsaturated ketones32
are also found to
work well as electrophiles.
However, in some cases under different reaction coniditions and with different
electrophiles, the spontaneous loss of water was not observed and product having
tetrahydrothiophene skeleton was isolated at the end of the reaction.30-33
For example; the alcohol 35 was isolated from the reaction of 2,5-dihydroxy-1,4-
dithiane (31) and methyl acrylate (34). Furthermore, the product was resistant to
dehydration so, Bishop and coworkers reacted the compound 35 with mesyl chloride
to eliminate water and obtain compound 36 (Scheme 12).30
In general, water can be
easily removed from system such as 35 or 37 by treatmant either with mesyl chloride
or TFAA.
11
11
Scheme 12 Formation route of the dihydrothiophene 36 structure
For example, if a nitro olefin is used as an electrophile, the resultant structure at the
end of the reaction will be compound 37. Treatment of compound 37 with
trifluoroacetic anhydride gave compound 38. Furthermore, an oxidizing agent like
DDQ31
provided further oxidation to thiophene structure 39. An example is
illustrated in Scheme 13.31
Scheme 13 Formation of compound 39 from 37
Moreover, enantioselective synthesis of tetrahydrothiophene ring was also published
recently.32
In this article; α,β-unsaturated carbonyl compounds bearing
tirfluoromethyl moieties were used as electrophiles due to the biological importance
of trifluoromethyl moiety.
Scheme 14 Enantioselective synthesis of tetrahydrothiophene structure 42
12
12
The chiral catalyst 41 used in this study is a bifunctional catalyst that activates the
electrophile 40 by donating hydrogen bonds and activates in-situ formed 2-
mercaptoacetaldehyde (32) molecule by abstracting the hydrogen bonded to sulfur.
Finally, the tetrahydrothiophene structure 42 containing three chiral centers was
formed (Scheme 14).
All the examples given above present tetrahydrothiophene structures that are
susceptible to dehydration however; there is also another study in which a modified
thiol 43 and trans-β-nitro styrene (44) were used, which resulted in a more stable
tetrahydrothiophene structure 46 (Scheme 15).33
The trick here was the usage of α,β-
unsaturated carbonyl compound as electron withdrawing group instead of carbonyl
group.
Scheme 15 Enantioselective synthesis of nitro group containing tetrahydrothiophene
structure 46
1.5 Michael addition of thiol compounds to α,β-alkynyl carbonyl compounds
It is also well-known that both aromatic and alkyl thiols can undergo Michael
addition reactions with α,β-alkynyl carbonyl compounds without any catalyst.
Although, thiolate anions are also capable of giving nucleophilic addition reaction
with alkynes with no adjacent electron withdrawing moiety,34
alkynes with electron
withdrawing groups undergo reactions at milder conditions.35-40
13
13
Michael addition of thiols to α,β-alkynyl carbonyl compounds also meet with the
criterias of click chemistry like high yield, regioselectivity, stereoselectivity, no by-
products so, therefore, this reaction is also called as a click reaction.36,40
Because of these merits, Michael addition of thiols to α,β-alkynyl carbonyl
compounds are used in materials chemistry applications.36
A study published by Truce et al.38
showed the wide scope of this reaction with
various electron withdrawing group moieties adjacent to alkynes (Scheme 16).
Moreover, Truce et al. also studied E/Z isomer ratios and found that Z isomer is
formed preferentially.
Scheme 16 Study by Truce et al. indicating the substrate scope of the reaction
1.6 Fiesselmann Thiophene Synthesis
Fiesselmann thiophene synthesis is a method for thiophene ring construction by
condensation reaction between alkyl thioglycolate 47 and α,β-alkynyl carbonyl
compounds. Scheme 17 summarizes the work done with alkyl thioglycolate 47 and
electrophiles 48, 50, 52, 54 for the synthesis of thiophene derivatives 49, 51, 53, 55.41
14
14
Scheme 17 Brief examples for substrate scope of Fiesselmann synthesis
1.6.1 Mechanism of the reaction between thioglycolic acid α,β-alkynyl carbonyl
compounds:
The generally accepted mechanism for this reaction begins with the addition of
methyl thioglycolate anion 56 to the alkyne carbon atom of dimethyl acetylene
dicarboxylate (57). Following this, the allenic enolate 58 is formed. After the proton
transfer, another methyl thioglycolate anion 56 attacks at the sulfur-bonded carbon
atom of the α,β-unsaturated carbonyl compound 59 and forms the dithioacetal
compound 60 (Scheme 18).
15
15
Scheme 18 First part of the mechanism of Fiesselmann synthesis
After two consecutive Michael addition reactions, NaOMe abstracts one of the
methylenic protons bonded to sulfur atom of compound 60. Then Dieckmann
condensation reaction takes place and methanol elimination occurs and compound 61
is formed. Since thiolate aninos are good leaving groups and NaOMe is a base that is
strong enough to facilitate E2 elimination, double bond is formed on the cyclic
compound 62 by E2 elimination. Lastly, following keto-enol tautomerization yields
the thiophene ring 63 (Scheme 19). It is important to note that all the steps here are
expected to be reversible since thiolate anion is both a good nucleophile and a good
leaving group. Details of this mechanism will be discussed in results & discussion
part.
16
16
Scheme 19 Second part of the mechanism of Fiesselmann synthesis
1.6.2 Histroical view of Fiesselmann thiophene synthesis:
Along the way of the discovery of Fiesselmann reaction, the chemical structure of
biotin was newly elucidated so, synthesis of tetrahydrothiophene skeleton had started
to gain importance. R. B. Woodward published the synthesis of 64 which utilizes
methyl thioglycolate (34) and methyl acrylate (56) in the presence of base to access
tetrahydrothiophene structure 64 (Scheme 20). 42
Scheme 20 Woodward's synthesis of tetrahydrothiophene ring 64
After eight years of Woodward’s publication, Fiesselmann adopted this system to
synthesis of 2,3,5 trisubstituted thiophenes.43
In the following years, Fiesselmann and
co-workers, other researchers46
applied this system for synthesis of various thiophene
structures.44,45,48
Later, a similar methodology was published for pyrrole, furan and
17
17
thiophene synthesis by Hendrickson et al.47
In this article the synthesis of furan 67,
thiophene 69 and pyrrole 71 derivatives were described by using dialkyl acetylene
dicarboxylate 65 as electrophile and α-heteroatom carbonyl compounds 66, 68, 70 as
nucleophiles (Scheme 21).
Scheme 21 Hendrickson’s general synthesis for heterocyclic ring construction
However; Fiesselmann published his works mostly as patents and doctoral theses so
that, scientific community was not truly aware of his studies. Obrecht et al.48
published a work in 1997, where the work of Fiesselmann was rediscovered without
giving citation to Fiesselmann’s previous works.41
1.6.3 New applications of Fiesselmann synthesis:
Nowadays Fiesselmann thiophene synthesis is recognized and still being studied. For
instance, Müller and co-workers first utilized thiophene diacyl chloride 72 for
Sonogashira coupling with 73 (Scheme 22). Then ethyl thioglycolate (74) was added
to the reaction mixture. This multi-component reaction yielded compound 75.49
In
18
18
another study they prepared unstable compound 76 and applied Sonogashira
coupling with 77. After, adding ethyl thioglycolate (74) yielded 78 which is a
constitutional isomer of 75.50
Both oligothiophenes 75 and 78 were found to be
useful molecules for materials chemistry applications.49,50
Scheme 22 Two alternative methods for accessing oligothiophenes 75, 78 by
Fiesselmann synthesis
Finally, an alternative method for a variation of Fiesselmann reaction was also
developed by using KF/Al2O3 as an inorganic base and PEG-400 (polyethylene
glycol) as a green solvent.51
Conversion of 79 into 80 was achieved in 80% yield
(Scheme 23).
Scheme 23 Fiesselmann synthesis of 80 from 79 with an inorganic base
19
19
1.7 Synthesis of 2,3-disubstituted thiophenes by cyclization reactions
Compounds containing thiophene moiety are particularly of interest in materials
chemistry, medicinal chemistry and natural product total synthesis. Therefore,
synthesis of 2,3-disubstituted thiophenes was also studied widely in the literature.
Due to the large number of methods for synthesis of 2,3-disubstituted thiophenes, the
reactions described in this part are limited to the synthesis of 2,3-disubstituted
thiophenes by cyclization reactions.
A classical example for the formation of 2,3-disubstituted thiophenes by cyclization
is the synthesis of benzothiophene (83). An early example utilized styrene (81) and
H2S (82) at high temperatures for the synthesis of benzothiophene (83) (Scheme
24).52
Scheme 24 Synthesis of benzothiophene (83) under harsh conditions
According to a recenty published method, benzothiophene (83) was obtained in 70%
yield by reaction of ((2-bromophenyl)ethynyl)silane (84) with Na2S.9H2O (85) at a
relatively lower temperature. (Scheme 25).53
Scheme 25 Synthesis of benzothiophene (83) under milder conditions
A different approach was developed by Katritzky and co-workers, for the synthesis
of 3-substituted 2-aminothiophene 89. Treatment of vinyl compound 86 with nBuLi,
20
20
followed by the reaction with isothiocyanate 87 gave a mixture of thioamides 88-a,
88-b. Then, the mixture of thioamides 88-a, 88-b were used without purification and
treated with ZnBr2 to yield 3-substituted 2-aminothiophenes 89 (Scheme 26).54
Scheme 26 Synthesis of 3-substituted 2-aminothiophene 89
In another study, O-ethyl S-(2-oxoethyl)carbonodithinote (92) was utilized as sulfur
source. The enolate 91 was formed by treatment of cyclohexanone (90) with
LiHMDS and ZnCl2. Then the enolate 91 was reacted with O-ethyl S-(2-
oxoethyl)carbonodithinote (92). Afterwards, the aldol product 93 was treated with 1-
methylpiperazine to form compound 94. Then treatment of 94 with HCl yielded
thiophene derivative 95 (Scheme 27).55
Scheme 27 Synthesis of thiophene 95
21
21
Moreover, there is also a metal induced strategy developed by Gabriele and co-
workers. By this methodology, 2,3-dimethyl thiophene (97) was prepared by
palladium catalyzed cycloisomerisation of (Z)-2-en-4-yne-1-thiol (96) Authors
claimed that alkyne was activated by coordination of palladium to the alkyne moiety.
Then nucleophilic attack of thiol yields the corresponding thiophene 97 (Scheme
28).56
Scheme 28 Synthesis of 2,3-dimethyl thiophene (97)
1.8 Aim of the thesis
The aim was to develop a new and efficient methodology to synthesize 2,3-
disubstituted thiopenes. To achieve this goal, first ketoalkynes will be synthesized
from readily available acyl chlorides and alkynes by Sonogashira coupling (Scheme
29).
Scheme 29 Synthesis of ketoalkynes
Then, the ketoalkynes will be reacted with 2,5-dihydroxy-1,4-dithiane (31) to form
alcohol intermediates. For formation of desired thiophene derivatives, alcohols will
be submitted to water elimination (Scheme 30).
Scheme 30 Synthesis of 2,3-disubstituted thiophenes from ketoalkynes
22
22
23
23
CHAPTER 2
RESULTS AND DISCUSSION
2.1 Synthesis of starting materials
Ketoalkynes were used as the starting materials for the synthesis of 2,3-disubstituted
thiophene derivatives. For the synthesis of ketoalkynes, readily available acyl
chlorides 98-100 and terminal acetylene derivatives 101-103 were utilized (Scheme
31).
Scheme 31 Readily available starting compounds
Ketoalkynes were synthesized by Sonogashira coupling of acyl chlorides 98-100 and
terminal alkynes 101-103 according to a literature procedure (Scheme 32).62
Homocoupling product was also formed as a minor product.
24
24
Scheme 32 Synthesis of ketoalkynes by Sonogashira coupling
The synthesized ketoalkynes (104-109) (Scheme 33) are known in the literature.62-68
Scheme 33 Sythesized ketoalkynes
2.1.1 Mechanism for Sonogashira coupling
Although the mechanism of Sonogashira coupling is not entirely understood, the
generally accepted catalytic cycle is shown in Scheme 34. The catalytic cycle begins
with the reduction of Pd(II) species to Pd(0). Then oxidative addition of Pd(0)
species to acyl halide occurs. A tetra coordinated palladium species is formed at the
end of this step. Then transmetallation of this tetracoordinated palladium species
with copper acetylide complex forms the palladium acetylide complex. Finally
reductive elimination of this palladium acetylide complex gives the final product and
regenerates the catalyst.
The second cycle begins with the coordination of copper to the triple bond.
Coordination of the copper increases the acidity of acetylenic proton. Then this
acetylenic proton is abstracted by the nitrogenous base and copper acetylide complex
is formed which is then used in the transmetallation step (Scheme 34).57
25
25
Scheme 34 Catalytic cycle for Sonogashira coupling
2.1.2 Interpretation of polarization of alknyl carbon atoms by 13
C NMR
chemical shift differences
An important feature of the ketoalkyes, that are synthesized as starting materials for
this synthesis, is the electron withdrawing moiety adjacent to alkyne that is crucial
for the reactivity. The experiments carried out with nonpolarized symmetrical triple
bonds didn’t give any reaction. Therefore, we turned our attention to the synthesis of
alkynes that are bearing an electron withdrawing moiety. So, it is well known that
due to the conjugation of π bonds, the β-carbon atom is expected to be more
electrophilic than the α-carbon atom with respect to the carbonyl group. This
phenomenon is also expected to be observed in the 13
C NMR spectra. The more
26
26
polarized triple bonds would show more difference in their chemical shift values.
The absolute values of 13
C NMR chemical shift differences of α- and β-carbon atoms
in ketoalkynes 104-109 are shown in Table 2.
Table 2 13
C NMR data for ketoalkynes 104-109
Compound 13
C NMR (101 MHz, CDCl3)
Chemical Shifts (ppm)
|∆ [(δ β-carbon) – (δ α-carbon)]|
104
6.2
6.2
6.0
17.2
0.5
0.3
105
106
107
108
109
This observed chemical shift differences is highly subsituent dependent. For
instance, in case of compounds 108 and 109 the difference in chemical shifts are
even less than 1 ppm whereas, for compound 107 the ∆δ value is 17.2 ppm.
If ∆δ ppm values of 105, 107, 108, 109 are considered it would provide a concise
result on effect of β-substitution on polarization. Because, all these compounds
contain benzoyl moiety and differ only in their β-position.
For instance, compound 109 has the lowest ∆δ ppm value. This trend is reasonable
considering the electron releasing effect of trimethyl silyl group. Second lowest ∆δ
ppm value belongs to hydrogen atom substituted compound 108. When the
27
27
electropositive nature of hydrogen atom is considered again it is not surprising that
the ∆δ ppm value is low compared to 105 and 107.
The comparison of compounds 105 and 107 clearly indicates the effect of
delocalization. Due to enhanced electron-releasing effect caused by conjugation
present in 105, this structure has less polarized alkyne moiety compared to 107.
2.2 Synthesis of the 2,3-disubstituted thiophenes from ketoalkynes
Reaction of 2,5-dihydroxy-1,4-dithiane (31) with corresponding ketoalkynes 104-109
in the presence of NEt3 as the base followed by treatmeant with silica gel yielded
2,3-disubstituted thiophenes 110-115 in good to excellent yields (Scheme 35).
Formation of 2,3-disubstituted thiophene ring was easily detected by measuring the
coupling constant J between the thiphene protons which has a characteristic value of
5.3 Hz. Synthesized 2,3-disubstituted thiophenes are shown in Scheme 36.
Scheme 35 Synthesis of 2,3-disubstituted thiophenes
Scheme 36 Synthesized 2,3-disubstituted thiophenes
28
28
2.3 Mechanistic considerations on the reaction between 2,5-dihydroxy-1,4-
dithiane and ketoalkyne
In this part two of the plausible mechanisms for the formation of alcohol product 122
is discussed with an emphasis on the first pathway.
2.3.1 First pathway
The suggested mechanism for this reaction begins with the base induced cleavage of
2,5-dihydroxy-1,4-dithiane (31) that forms the corresponding thiolate salt 116
(Scheme 37).
Scheme 37 Base induced fragmentation of 2,5-dihydroxy-1,4-dithiane
Then, the highly nucleophilic thiolate anion 116 attacks the β-carbon atom of the
ketoalkyne 117. After the proton transfer from trimethyl hydrogen cation to vinyl
anion, thioenol ether 118 is formed and NEt3 is regenerated. Next step is the attack of
another thiolate salt 116 on β-carbon atom of thioenol ether 118 to form thioacetal
119. This step produces two acidic hydrogen atoms at the α-position of carbonyl
moiety of thio acetal 119 (Scheme 38).
29
29
Scheme 38 Formation of thioacetal 119 as an intermediate
Abstraction of this hydrogen atom by NEt3 forms the enolate 120. Then attack of the
enolate 120 to aldehyde carbon atom, forms the tetrahydrothiophene intermediate
121 and regenerates NEt3 after proton transfer step. Since thiolate groups are
excellent leaving groups, NEt3 induced elimination yields relatively stable alcohol
intermediate 122 and regenerates thiolate anion 116 (Scheme 39).
Scheme 39 Formation of alcohol 122 intermediate
Effect of the selective enolization on the product formation
The thioacetal intermediate 119 contains 2 different carbonyl goups. First one is the
two equivalent aldehyde groups, second one is the ketone group. It is known from
the literature that, if there are two enolizable carbonyl groups, the enol form of the
less electrophilic carbonyl group attacks the more electrophilic carbonyl group. The
thioacetal intermediate 119 shown in Scheme 40 follows this general trend. The enol
form of the keto group attacks the aldehyde group (Scheme 40). If the reaction was
proceeded over enolization of aldehyde and the attack to the ketone, the trisubstituted
thiophene 125 would be formed. Formation of the product 125 was not detected in
any reaction (Scheme 40).
30
30
Scheme 40 An inoperative mechanism for enolization of 119
However, when Obrecht and co-workers reacted ketoalkyne 126 with methyl
thioglycolate (56) in the presence of Cs2CO3 and MgSO4, the product was a
trisubstituted thiophene 129 (Scheme 41).48
Authors claimed that intermediates 127
and 128 were formed at the end of the first reaction. Then Cs2CO3, MgSO4 and
MeOH were added and a trisubstituted thiophene 128 was formed. For this example,
formation of trisubstituted thiophene can be explained by the same trend also. Enol is
formed at the ester group and attack occurs to the keto group which is more
electrophilic. It is important to note that, the authors did not provide any
spectroscopic data showing the formation of 127 and 128.
Scheme 41 Reaction of 126 with 56
The authors did not suggest a mechanism for this reaction. Our suggestion for the
formation of trisubstituted thiophene 129 is depicted in Scheme 42.
31
31
Scheme 42 Suggested mechanism for formation of 129
2.3.2 Second Pathway
There is also another pathway that is worth to be discussed. This pathway is the
intermolecular attack of thiol enol ether moeity to the aldehyde group in compound
118 (Scheme 43). This pathway also seems to be plausible when several factors are
taken into account. First of all, the nucleophilicty of the α-carbon atom with respect
to carbonyl group. This carbon atom is expected to show nucleophilic character
because, this carbon atom is at the β-position with respect to sulfur atom of thio vinyl
structure at the same time. Moreover the electrophile is an alkyl aldehyde carbon
atom which is expected to show high electrophilicty. Furthermore, this pathway
operates through intermolecular attack.
Scheme 43 Second pathway for formation of alcohol intermediates 122
2.3.3 Evaluation of the two pathways
However, an investigation of the literature showed that first pathway seems to be
more plausible than second pathway.
For instance, Fiesselmann synthesis42
that is depicted in introduction part scheme 18,
operates through the attack of sceond thiolate group on the β-carbon atom of thioenol
ether 59 to form thioacetal 60. Moreover in an article58
the equilibrium between the
32
32
β-sulfido-α,β-unsaturated ketones and thioacetals are studied. In this study authors
found that the reaction between compound 133 and 134 in the presence of NEt3
produced 6 compounds (133 + 134 135, 136, 137, 138) which were found to
be in equilibrium (Scheme 44).
Scheme 44 The equilibrum reaction of 133 and 134
From that information, a similar equilibrium would also be expected in the reaction
of 116 and 117 in the presence of NEt3 also.
On the other hand in an article59
published by Fevig et al. compound 140 was
isolated from reaction of 68 with 139. Fevig et al. reported that reaction did not
proceed further after the formation of 140. However, it was important to note that the
electrophile in this reaction was a ketone which is less reactive than aldehyde.
Furthermore, there is no base in the reaction medium (Scheme 45).
33
33
Scheme 45 Reaction between 68 and 139
2.4 Stability of the alcohol intermediates
The alcohol intermediates 122 formed were treated with SiO2 to eliminate water and
form the thiophene 141 (Scheme 46).
Scheme 46 Formation of thiophene 141 from alcohol derivatives 122
The alcohol intermediates 122 underwent a slow dehydration which led to the
prolonged reaction times. They were also not stable in CDCl3 solvent.
In addition to silica gel induced dehydration of alcohol intermediates 122, washing
the alcohol intermediates 122 with acidic water solution also caused dehydration.
The tendency for the dehydration of alcohol intermediates 122 was to generate
aromatic thiophene ring 141. However, the dehydration process needs at least a
solvent to proceed rather than occuring spontaneously.
Due to the instability of alcohol intermediates 122 on silica gel, full characterization
of these compounds were not studied and the alcohols 141 were detected in all crude
NMR spectra.
34
34
Figure 1 1H NMR spectrum of the alcohol 142
In Figure 1, the 1H NMR spectrum of the alcohol 142 is presented. In addition to the
broad alcohol signal resonating between Ha and Hb resonance signals, the chemical
shifts and splitting patterns of Ha, Hb and Hc also support the proposed structure. The
geminal methylene protons resonate as an AB-system. Both parts of the AB-systems
are further split into doublets due to the coupling with the adjacent Hc proton. The
coupling constants and the chemical shifts of these protons are presented in the Table
3.
Table 3 Spectral data for alcohol 142
Proton 1H NMR (400 MHz, CDCl3) Chemical
Shifts (ppm) and Coupling Constants
(Hz)
Ha 3,57 ppm Hb 3,27 ppm Hc 5,53 ppm
Ja,c = 7.6 Hz Jb,c = 2.9 Hz Ja,b = 12.9 Hz
35
35
It should be also noted that trans and geminal coupling constants reported in the
Table 3 are in well agreement with the literature values of tetrahydrothiophene ring,
however; the cis coupling which is 2.9 Hz is remarkably lower with respect to the
reported literature value which is 5.4 Hz.60
2.5 Hydrolysis of trimethyl silyl group
The two compounds 109 and 115 that were bearing trimethyl silyl groups in their
structures were found to be partially hydrolyzed in the reaction medium. It is known
from the literature, that trimethyl silyl groups are sensitive to mildly basic
conditions.61
Therefore, the presence of triethyl amine in the reaction medium may
have triggered the decomposition of both compounds 109 and 115. Especially, the
presence of triethylammonium hydroxide (143) as impurity in triethyl amine may be
responsible for hydrolysis of trimethylsilyl group (Scheme 47).
Scheme 47 Possible hydrolysis pathway for compounds 109 and 115
36
36
37
37
CHAPTER 3
CONCLUSION
Since, the importance of thiophene derivatives not only for synthetic organic
chemistry but also for medicinal chemistry and materials chemistry is noteworthy,
we aimed to develope a new facile methodology to access 2,3-disubstituted
thiophenes.
In the first step ketoalkyne derivatives were synthesized by Sonogashira coupling of
acyl chlorides and terminal alkynes in good yields (Scheme 48).
In the second step, the 2,3-disubstituted thiophene ring was formed by cyclization
reaction of 2,5-dihydroxy-1,4-dithiane (31) and corresponding ketoalkynes in the
presence of base followed by dehydration by silica (Scheme 49).
38
38
Scheme 48 Synthetic scheme for synthesis of ketoalkynes 104-109
39
39
Scheme 49 Synthesis of 110 – 114
40
40
As a conclusion, a new two-step methodology was developed for a facile synthesis
of 2,3-disubstituted thiophene derivatives starting from readily available compounds.
The yields were good to excellent for both steps.
41
41
CHAPTER 4
EXPERIMENTAL
4.1 General
Nuclear magnetic resonance (1H NMR and
13C NMR) spectra were recorded on a
Bruker Instrument Avance Series-Spectrospin DPX-400 Ultrashield instrument
CDCl3 with TMS as internal reference. Chemical shifts (δ) were expressed in units
parts per million (ppm). Spin multiplicities were specified as singlet (s), doublet (d),
doublet of doublets (dd), triplet (t), quintet (quint), hextet (h), multiplet (m), broad
doublet (bd), broad triplet (bt) and coupling constants (J) were reported in Hertz
(Hz).
Infrared spectra were recorded on a Thermo Smart Nicolet iS10 FT-IR spectrometer
equipped with ATR accessory. Band positions were reported in reciprocal of
centimeters (cm-1
).
High resolution Mass spectra were recorded by Agilent 1200/6210 LC-MS TOF with
electrospray ionization detector.
Column chromatographic separations were performed by using Fluka silica gel 60
plates with a particle size of 0.063–0.200 mm. Thin layer chromatography (TLC)
was performed by using 0.25 mm silica gel plates purchased from Fluka.
Naming of the compounds were done by ACD NMR (Name generator).
42
42
4.2 General procedure for the synthesis of ketoalkyne derivatives 104-109
Ketoalkynes were prepared according to a literature method with slight
modifications.62
Pd(PPh3)2Cl2 (19 mg, 0.028 mmol) and CuI (11 mg, 0.056 mmol) in
THF (5 mL) were stirred under N2 atomsphere for 30 min. Then 0.2 mL (1.42 mmol)
of triethylamine, 1.42 mmol of acyl chloride, and alkyne (1.7 mmol) were added
respectively. The reaction was stirred for 3 h at room temperature. After the reaction
was completed, the solvent was evaporated, and the residue was treated with 25 mL
of diethyl ether. Then, the diethyl ether solution is passed through a pad of celite.
The celite was washed with diethyl ether (3 50 mL). Then, the filtrate and diethyl
ether solutions were combined and was washed with water (3 50 mL). Afterwards,
the organic layer was dried over MgSO4 and concentrated under reduced pressure.
Finally, the crude residue was subjected to column chromatography. Gradient elution
starting from hexane to hexane/ EtOAc (3:1) was employed for the purification of
desired ketoalkynes.
4.2.1 4,4-Dimethyl-1-phenylpent-1-yn-3-one (104): (Yellow oil, 82%, 217 mg) .
This compound is known in the literature and the spectroscopic data are consistent
with the literature values.63
1H NMR (400 MHz, CDCl3) δ 7.56 (bd, J = 6.9 Hz, 2H), 7.43 (bt, J = 7.4 Hz 1H),
7.36 (bt, J = 7.4 2H), 1.19 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 194.3, 133.0, 130.6, 128.7, 120.3, 92.3, 86.1, 44.9,
26.2.
IR (ATR, cm-1
) 2969, 2196, 1660, 1284, 1070, 1011, 757, 688.
43
43
4.2.2 1,3-Diphenylprop-2-yn-1-one (105): (Yellow oil, 85%, 247 mg) This
compound is known in the literature and the spectroscopic data are consistent with
the literature values.62
1H NMR (400 MHz, CDCl3) δ 8.23 (bd, J = 7.1 Hz, 2H), 7.72 -7.67 (m, 1H), 7.64
(bt, J = 7.4 Hz 2H), 7.55 -7.53 (m, 2H), 7.51 - 7.46 (m, 1H), 7.43 (bt, J = 7.3 Hz 2H).
13C NMR (101 MHz, CDCl3) δ 178.1, 136.9, 134.2, 133.2, 130.9, 129.7, 128.8,
128.7, 120.2, 93.2, 87.0.
IR (ATR, cm-1
) 2196, 1637, 1284, 1028, 1011, 994 731, 688.
4.2.3 1-(Naphthalen-2-yl)-3-phenylprop-2-yn-1-one (106): (Pale yellow solid,
74%, 268 mg, mp: 91-93 ºC) This compound is known in the literature and the
spectroscopic data and melting point data are consistent with the literature values.62,67
1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.21 (dd, J = 8.6, 1.6 Hz, 1H), 8.01 (d, J
= 8.0 Hz, 1H), 7.89 (t, J = 8.8 Hz, 2H), 7.74 (dd, J = 8.0, 1.2 Hz, 2H), 7.65 - 7.54 (m,
2H), 7.53 - 7.40 (m, 3H).
13C NMR (101 MHz, CDCl3) δ 178.0, 136.2, 134.4, 133.1, 132.7, 132.4, 130.9,
129.9, 129.1, 128.8, 128.6, 128.0, 127.0, 124.0, 120.2, 93.1, 87.1.
IR (ATR, cm-1
) 2201, 1622, 1303, 1285, 1166, 1125, 756, 724, 688.
44
44
4.2.4 1-Phenylhept-2-yn-1-one (107): (Yellow oil, 78%, 206 mg) This compound is
known in the literature and the spectroscopic data are consistent with the literature
values.63
1H NMR (400 MHz, CDCl3) δ 8.14 (bd, J = 8.5 Hz, 2H), 7.59 (bt, J = 7.4 Hz 1H),
7.47 (bt, J = 7.6 Hz, 2H), 2.50 (t, J = 7.1 Hz, 2H), 1.66 (quint, J = 7.3 Hz, 2H), 1.51
(h, J = 7.4 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 178.4, 137.1, 134.0, 129.7, 128.6, 97.0, 79.8, 30.0,
22.2, 19.0, 13.6.
IR (ATR, cm-1
) 2958, 2932, 2200, 1641, 1262, 698.
4.2.5 1-Phenylprop-2-yn-1-one (108): (Obtained as the side product from reaction
of trimethyl silyl acetylene and benzoyl chloride. Brown solid, 19%, 80 mg, from
reaction with 3.2 mmol acyl chloride, mp 48-50 oC). This compound is known in the
literature and the spectroscopic data and melting point data are consistent with the
literature values.65,66
1H NMR (400 MHz, CDCl3) δ 8.16 (bt, J = 8.5 Hz, 2H), 7.64 (tt, J = 7.4, 1.2 Hz,
1H), 7.50 (t, J = 7.7 Hz, 2H), 3.45 (s, 1H).
13C NMR (101 MHz, CDCl3) δ 177.5, 136.3, 134.7, 129.8, 128.8, 80.9, 80.4.
IR (ATR, cm-1
) 3233, 2092, 1635, 1594, 1579, 1451, 1314, 1245, 1174, 1001, 733,
713, 691.
45
45
4.2.6 1-Phenyl-3-(trimethylsilyl)prop-2-yn-1-one (109): (Obtained as the major
product from reaction of trimethyl sillyl acetylene and benzoyl chloride. Yellow oil,
70%, 450 mg, from reaction with 3.2 mmol acyl chloride ) This compound is known
in the literature and the spectroscopic data are consistent with the literature values.64
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.0 Hz 2H), 7.44 (t, J = 7.4 Hz, 1H),
7.32 (t, J = 7.7 Hz, 2H), - 0.15 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 177.8, 136.6, 134.3, 129.8, 128.7, 101.0, 100.7, -0.6.
IR (ATR, cm-1
) 2962, 2153, 1625, 1244, 1035, 1016, 760, 699, 662.
4.3 General procedure for the synthesis of 2,3-disubstituted thiophene
derivatives 110-115
Ketoalkyne (0.5 mmol) was dissolved in 2 mL of DMF. Then 2,5-dihydroxy-1,4-
dithiane (0.25 mmol, 38 mg) and triethylamine (0.5 mmol, 70 µL) were added
respectively. After the addition of triethyl amine, the colour of the solution rapidly
turned into black and may get warm. After 15 min., the reaction was completed. The
reaction mixture was diluted with 20 mL of water and extracted with dietyl ether (3
20 mL). Then, the combined organic layers were washed with water (3 50 mL) to
remove residual DMF. The organic layer is seperated and dried over Na2SO4, the
crude residue was concentrated under reduced pressure. Then, the residue was
diluted with 10 mL of ethyl acetate and about 250 mg silica gel is added. The
heterogenous mixture was stirred overnight. After the reaction was stopped, the
heterogeous mixture was filtrated. The solid was washed with ethyl acetate (3 10
mL). Finally, the combined ethyl acetate portions were dried over Na2SO4 and
concentrated at reduced pressure to yield the desired compounds.
46
46
4.3.1 2,2-Dimethyl-1-(2-phenylthiophen-3-yl)propan-1-one (110): (Yellow oil,
79%, 96 mg)
1H NMR (400 MHz, CDCl3) δ 7.43 - 7.39 (m, 2H), 7.39 - 7.31 (m, 3H), 7.28 (d, J5,4
= 5.3 Hz, 1H, H-5), 7.02 (d, J4,5 = 5.3 Hz, 1H, H-4), 1.07 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 211.5, 142.3, 137.8, 134.1, 128.9, 128.8, 128.3,
127.2, 124.7, 45.4, 27.0.
IR (ATR, cm-1
) 2966, 2868, 1684, 1272, 1047, 1006, 867, 722, 695, 665.
HRMS analysis: m/z (M+H)+ for C15H16OS calculated: 245.0995, detected:
245.1058.
4.3.2 Phenyl(2-phenylthiophen-3-yl)methanone (111): (Brown oil, 91%, 120 mg)
1H NMR (400 MHz, CDCl3) δ 7.67 (bd, J = 8.4 Hz, 2H), 7.34 (bt, J = 7.4 Hz, 1H),
7.27 – 7.23 (m, 2H), 7.25 (d, J5,4 = 5.3 Hz, 1H, H-5), 7.21 (d, J4,5 = 5.3 Hz, 1H, H-4),
7.21 (t, J = 7.7 Hz, 1H), 7.15 - 7.09 (m, 4H).
13C NMR (101 MHz, CDCl3) δ 193.1, 147.8, 137.6, 136.6, 133.1, 132.8, 130.2,
129.9, 129.2, 128.4, 128.3, 128.2, 124.6.
IR (ATR, cm-1
)1650, 1596, 1276, 858, 761, 691, 674.
HRMS analysis: m/z (M+H)+ for C17H12OS calculated: 265.0682, detected:
265.0684.
47
47
4.3.3 2-Naphtyl(2-phenylthiophen-3-yl)methanone (112): (Brown oil, 89%, 139
mg)
1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.92 (dd, J = 8.6, 1.5 Hz, 1H), 7.84 -
7.76 (m, 3H), 7.58 - 7.52 (m, 1H), 7.48 (t, J = 7.3 Hz, 1H) 7.41 - 7.36 (m, 3H), 7.34
(d, J = 5.2 Hz, 1H,), 7.21 -7.09 (m, 3H).
13C NMR (101 MHz, CDCl3) δ 193.1, 147.7, 136.9, 135.5, 135.0, 133.3, 132.5,
132.3, 130.3, 129.6, 129.2, 128.6, 128.5, 128.3, 128.3, 127.8, 126.7, 125.2, 124.7.
IR (ATR, cm-1
)1650, 1624, 1371, 1283, 1122, 755, 727, 693.
HRMS analysis: m/z (M+H)+ for C21H14OS calculated: 315.0838, detected:
315.0844.
4.3.4 (2-Butylthiophen-3-yl)(phenyl)methanone (113): (Yellow oil, 91%, 111 mg)
1H NMR (400 MHz, CDCl3) δ 7.79 (bd, J = 8.4, 2H), 7.56 (bt, J = 7.4 Hz 1H), 7.46
(bt, J = 7.5 Hz 2H), 7.10 (d, J5,4 = 5.3 Hz, 1H, H-5), 7.08 (d, J4,5 = 5.3 Hz, 1H, H-4),
3.07 (t, J = 7.8 Hz, 2H), 1.69 (quint, J = 7.7 Hz, 2H), 1.38 (h, J = 7.4, Hz, 2H), 0.90
(t, J = 7.4 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 192.3, 139.4, 135.8, 132.5, 130.0, 129.6, 128.4,
121.3, 34.2, 31.0, 29.1, 22.5, 13.9.
IR (ATR, cm-1
)2956, 2927, 1649, 1514, 1444, 1266, 853, 694, 670.
HRMS analysis: m/z (M+H)+ for C15H16OS calculated: 245.1011, detected:
245.0995.
48
48
4.3.5 Phenyl(thiophen-3-yl)methanone (114): (Obtained as the side product from
the reaction of 109 with 2,5-diydroxy-1,4-ditihane after 5 h) (Dark brown oil, 7 mg,
8%) This compound is known in the literature and the spectroscopic data are
consistent with the literature values.68
1H NMR (400 MHz, CDCl3) δ
7.93 (dd, J2.5 = 2.9, J2.4 = 1.2 Hz, 1H, H-2 ), 7.84 (d
J = 7.0 Hz, 2H), 7.60 (dd, J4,5 = 5.0, J4,2 = 1.1 Hz, 1H, H-4), 7.57 (t, J = 7.4 Hz,
1H), 7.49 (t, J = 7.5 Hz, 2H), 7.38 (dd, J5,4 = 5.1, J5,2 = 2.9 Hz, 1H, H-5).
13C NMR (101 MHz, CDCl3) 190.1, 141.4, 138.7, 134.1, 132.4, 129.5, 128.7, 128.5,
126.3.
IR (ATR, cm-1
) 1646, 1509, 1408, 1274, 1137, 856, 820, 781, 695, 671.
4.3.6 Phenyl(2-(trimethylsilyl)thiophen-3-yl)methanone (115): (Obtained as the
major product from the reaction of 109 with 2,5-diydroxy 1,4-ditihane after 5 h.
Brown oil, 80%, 104 mg)
1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.0 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H),
7.53 (d, J5,4 = 4.8 Hz, 1H, H-5), 7.47 (t, J = 7.5 Hz, 2H), 7.37 (d, J4,5 = 4.8 Hz, 1H,
H-4), 0.39 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 192.1, 150.0, 146.8, 139.3, 132.4, 131.9, 129.7,
129.5, 128.4, 0.0.
IR (ATR, cm-1
) 2952, 1650, 1393, 1247, 1017, 837, 709, 694, 619.
49
49
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Figure A1 1H NMR spectrum of compound 104
AP
PE
ND
IX A
SP
EC
TR
AL
DA
TA
54
54
Figure A2 13
C NMR spectrum of compound 104
55
55
Figure A3 IR spectrum of compound 104
56
56
Figure A4 1H NMR spectrum of compound
57
57
Figure A5 13
C NMR spectrum of compound 105
58
58
Figure A6 IR spectrum of compound 105
59
59
Figure A7 1H NMR spectrum of compound 106
60
60
Figure A8 13
C NMR spectrum of compound 106
61
61
Figure A9 IR spectrum of compound 106
62
62
Figure A10 1H NMR spectrum of compound 107
63
63
Figure A11 13
C NMR spectrum of compound 107
64
64
Figure A12 IR spectrum of compound 107
65
65
Figure A13 1H NMR spectrum of compound 108
66
66
Figure A14 13
C NMR spectrum of compound 108
67
67
Figure A15 IR spectrum of compound 108
68
68
Figure A16 1H NMR spectrum of compound 109
69
69
Figure A17 13
C NMR spectrum of compound 109
70
70
Figure A18 IR spectrum of compound 109
71
71
Figure A19 1H NMR spectrum of compound 110
72
72
Figure A20 13
C NMR spectrum of compound 110
73
73
Figure A21 IR spectrum of compound 110
74
74
Figure A22 1H NMR spectrum of compound 111
75
75
Figure A23 13
C NMR spectrum of compound 111
76
76
Figure A24 IR spectrum of compound 111
77
77
Figure A25 1H NMR spectrum of compound 112
78
78
Figure A26 13
C NMR spectrum of compound 112
79
79
Figure A27 IR spectrum of compound 112
80
80
Figure A28 1H NMR spectrum of compound 113
81
81
Figure A29 13
C NMR spectrum of compound 113
82
82
Figure A30 IR spectrum of compound 113
83
83
Figure A31 1H NMR spectrum of compound 114
84
84
Figure A32 13
C NMR spectrum of compound 114
85
85
Figure A33 IR spectrum of compound 114
86
86
Figure A34 1H NMR spectrum of compound 115
87
87
Figure A35 13
C NMR spectrum of compound 115
88
88
Figure A36 IR spectrum of compound 115